This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures.

BAYAT eT Al | INTRODUCTIONGlycosylphosphatidylinositol (GPI) is a glycolipid that is synthetized and transferred to proteins in the membrane of the endoplasmic reticulum. 1 Biogenesis of GPI-anchored proteins (GPI-APs) is a conserved posttranslational mechanism in eukaryotes and is important for attaching these proteins to the cell membrane and for protein sorting, trafficking, and dynamics. 1,2 GPI synthesis and GPI-AP modification are mediated by at least 31 genes, and pathogenic variants in 22 of these genes have been associated with human disease to date. 3 The X-linked phosphatidylinositol glycan class A protein gene (phosphatidylinositol glycan class A protein [PIGA]) is part of a heptameric enzyme complex catalyzing the transfer of N-acetylglucosamine (GlcNAc) to phosphatidylinositol as the first step in GPI anchor biosynthesis. [4][5][6] In contrast to other members of the GPI-GlcNAc transferase complex, PIGA is an integral membrane protein with only one transmembrane domain residing in the endoplasmic reticulum (ER). The large N-terminal cytoplasmic domain contains two Rossmann folds. 7 Pathogenic germline missense variants in PIGA are associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (OMIM 316818). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] The affected

We describe five boys from different families with an atypically severe form of Pelizaeus-Merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. Patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. Gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.

52Background: Glycosylphosphatidylinositol Biosynthesis Defects (GPIBDs) cause a group of 53

BackgroundGlycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification.MethodsWe studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals.ResultsWe found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD.ConclusionsDue to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0510-5) contains supplementary material, which is available to authorized users.